Abstract
Gene expression and secretion of the cardiac polypeptide hormones atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP) are simultaneously upregulated in various cardiac disorders such as congestive heart failure, ischemic heart disease, and hypertensive heart disease, in which hemodynamic or neuroendocrine changes are key components in the progression of disease. However, during acute cardiac allograft rejection, plasma BNP levels are increased but not those of ANF. Successful treatment of the rejection episode decreases the elevated plasma BNP to prerejection values suggesting that substances related to inflammation may selectively influence BNP gene expression. Indeed, cytokines such as TNFα and IL-1β selectively stimulate cardiac BNP at the transcriptional and translational levels in cardiomyocyte cultures without affecting ANF. This selective BNP increase is seen in vivo, in addition to acute cardiac allograft rejection, in several circumstances where inflammation significantly contributes to the pathogenesis of disease such as in sepsis and in acute myocarditis.
Highlights
Seven years after the discovery of the natriuretic factor from the atria of the heart (ANF) [1, 2] and five years after the first purification and sequencing of its circulating form [3], brain natriuretic peptide (BNP) was isolated from porcine brain [4]
In a study of 69 consecutive allograft cardiac recipients, we found that plasma BNP and NT-proBNP levels in patients with endomyocardial biopsies graded 3 according to the International Society of Heart and Lung Transplantation (ISHLT) were significantly higher than those in ISHLT grade 0 to 2
In the aforementioned study on transplant patients conducted in our laboratory, plasma IL-1β or TNF-α levels did not increase during acute rejection episodes, and further IL-1β and TNF-α blood levels did not correlate with BNP levels [17], nor does the conditioned medium from mixed lymphocyte reaction (MLR) cultures have detectable amounts of IL-1β or TNF-α suggesting that substances other than proinflammatory cytokines are responsible for the selective upregulation of BNP in inflammation
Summary
Seven years after the discovery of the natriuretic factor from the atria of the heart (ANF) [1, 2] and five years after the first purification and sequencing of its circulating form [3], brain natriuretic peptide (BNP) was isolated from porcine brain [4]. Replacement of the failing ventricle as it is done in orthotropic heart transplantation does not result in normalization of either BNP or ANF plasma levels even after normalization of intracardiac pressures and the renin angiotensin aldosterone system occurs [15,16,17,18] This finding argues against an important ventricular contribution to circulating NP levels. In studies comparing the diagnostic value for detecting systolic or diastolic heart failure or for assessing mortality in patients with chronic congestive heart failure, BNP appeared to fare better as a biomarker than ANF [19,20,21,22,23] Following these observations, BNP or NT-proBNP has been used most commonly as diagnostic or prognostic biomarkers for a variety of cardiac disorders including myocardial remodeling [24], asymptomatic left ventricular dysfunction [25], sudden cardiac death and ventricular arrhythmia [26], and acute pulmonary embolism [27]. There are subtle differences between ANF and BNP, the stimuli for production and secretion of these two hormones have been considered almost identical until a discoordinated change of ANF and BNP was revealed in allograft rejection episodes as described in the following
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